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3 Methodology As might be judged from the preceding chapter's discussion of the nature of cancer, it will not be easy to determine what causes cancer. It is especially difficult to identify the connections between cancer and what people eat, not only because of the complex nature of the dis- ease, but also because of the complex nature of the food supply, the variations in eating habits, and the limitations of scientific tools. The classic diet-related disease is associated with a deficiency of one or more nutrients. The discoveries of the causes and cures of dis- eases such as scurvy (caused by a lack of ascorbic acid) and beriberi (caused by a lack of thiamine) led to the development of a specific model for nutrition research in which nutrient requirements were determined by producing deficiencies in laboratory animals or volunteers. The relationships between diet and chronic disease did not emerge as a major interest to investigators until the causes of the princi- pal deficiency diseases were identified. Just as it was once difficult for investigators to recognize that a symptom complex could be caused by the lack of a nutrient, so until recently has it been difficult for scientists to recognize that certain pathological conditions might re- sult from an abundant and apparently normal diet. Adverse effects on health associated with nutrient excess in humans have long been recog- nized. Obesity is the most noticeable among them. Other adverse effects result, at least partly, from the availability (and overuse) of vitamin and mineral supplements. Certain vitamins and most of the minerals are known to be toxic above certain levels. But these known adverse (patho- logic) effects of vitamin and mineral overdoses have, like the deficiency diseases, a conspicuously direct relationship with the nutrients in ques- tion. That is, the effects of denying or restoring a nutrient to an ex- perimental subject, whether animal or human, are usually observable within a short time--at most, months. The links between diet and meta- bolic, degenerative, and malignant diseases are considerably less obvious. However, because such conditions as atherosclerosis or cancer are probably associated with dietary patterns that extend over a number of years, the causative agents are difficult to identify. The possible relationships between diet and cancer have been investi- gated in studies of human populations and in laboratory experiments using various in vitro systems (to check substances for their ability to mutate bacteria and mutate or transform other cells) or animal models (to test substances directly for carcinogenicity). This chapter provides a synop- sis of the strengths and weaknesses that are inherent in the methods used 30 3-1

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Methodology 31 to study these relationships. It also explains the approach adopted by the committee in evaluating the epidemiological and experimental evidence. EPIDEMIOLOGICAL METHODS General Approaches In epidemiological research on cancer and diet, investigators seek to associate exposure to dietary risk factors with the occurrence of cancer in defined population groups. The studies are largely observational, and may be of several different types: Descriptive Studies. These studies describe the patterns of disease occurrence in one or more populations, in components of the same popula- tion, or in a single population over time. The observed patterns may be related to certain other environmental variables or characteristics of the population, such as demographic factors, industrial pollution, or diet. Data from descriptive studies are suggestive, rather than defini- tive, and serve primarily to identify population groups at risk and to generate hypotheses for further investigation. Correlation Studies. These studies, based on aggregate exposure data and observed outcomes, provide the next step in establishing mean- ingful associations. The crudest of these studies are ecological studies in which national per capita food intake is related to patterns of can- cer incidence or mortality. This type of analysis is frequently able to utilize existing data and is a valuable tool for generating new hy- potheses. At a more refined level, interviews with carefully selected individuals may be correlated either with group-specific cancer rates or with regional differences in rates. In such analyses, the data on expo- sure and those on outcome may be representative of exposure of differ- ent groups in the population. Consequently, they often do not reflect true individual associations and thus may be misleading. This is often referred to as an ecological fallacy. C~c--~nntrn1 Studies. Unlike descriptive and correlation studies, case-control studies enable investigators to collect data for individuals rather than for groups, and they are designed to control for confounding variables. In these studies, exposure data (such as dietary intake) are collected for cases with a specific type of cancer and are then compared with similar exposure data for a suitably selected noncancer group, usually referred to as "controls" or compeers. Differences in exposures between the two groups that cannot be accounted for by chance occurrence (random errors) or by known biases (systematic errors) represent true associations between individual exposure and disease and may actually reflect causal relationships (Ibrahim, 1979; MacMahon and Pugh, 1970~. The strength of the association can be measured by an odds ratio calculated from a 2 by 2 contingency table. 3 - 2

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32 DIET, NUTRITION, AND CANCER Cohort Studies. Similar to case-control studies, cohort studies focus on individuals and control for confounding variables. Furthermore, they are less susceptible to bias than case-control studies because the exposure data are collected prior to the occurrence of the disease. In the simplest cohort studies, occurrence rates of disease (e.g., cancer) over time are compared between two groups of individuals with similar characteristics but with different histories of exposure (e.g., none vs. any; low vs. high) to the factors being studied. Higher or lower inci- dence of disease in one group relative to the other implicates the expo- sure variable as playing a role in the etiology of the disease. Cohort studies are reported relatively infrequently because the low incidence of the disease requires following large groups for long periods. This neces- sitates considerable expenditures of both time and money. Furthermore, even if a cohort study is prospective, it is limited in that the cohorts were self-selected and were not randomly assigned as in true clinical trials or intervention studies. However, dietary intake data from sev- eral cohort studies of coronary heart disease have enabled investigators to perform retrospective cohort analyses of diet and cancer (see Chapter 5~. Intervention Studies. In these studies, which are sometimes called experimental studies, the investigator randomly assigns the subjects to two (or more) groups, which are then exposed (or not exposed) to differ- ent levels of the substance being studied. Although such studies are ideal for establishing true causal relationships, opportunities for con- ducting this type of study are rare. In the past, intervention studies have most often been undertaken to test the effectiveness of vaccination programs or new treatments for disease. Their use in future research on diet and cancer will be discussed in a second report to be prepared by this committee. Methods For Determining Dietary Intake Several standard methods with markedly different levels of precision are used to determine what people eat. Some of these methods are based on government production statistics; others use information obtained from individuals about what they have purchased, prepared, or eaten. Group Dietary Data. Comparisons of diets for different population groups are generally based on one or two types of data: national per capita food intakes (also called food disappearance data) or house- hold food inventories. Most cross-national studies of cancer incidence comparing national per capita "intake" of various foods or nutrients are based on figures derived from food balance sheets. The intakes are calculated by adding the total quantity of food produced in a country to the quantity of food imported, and then subtracting the sum of food exported, fed to live- stock, put to nonfood uses, and lost in storage. These estimates are 3-3

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Methodology 33 then divided by the total population to yield per capita intakes. Comparisons of cancer rates at various sites with national per capita intakes of, for example, fat, fiber, and animal protein are derived from data such as these. Although national per capita intakes have been very useful in providing leads for further research, they are inaccurate as measures of food that has actually been eaten. They really only measure food that has "disappeared" into the food supply--which is why they are sometimes called "food disappearance data." They do not account for food produced by individuals, for waste in stores, restaurants, or homes, or for differences in consumption within a country by different age and sex groups. In this report, the term "per capita intake" is used synonymously with "food disappearance data." Household food inventories are used in epidemiological studies . to obtain data on the eating patterns of groups of persons who dif- fer geographically, socioeconomically, ethnically, or in other ways. Food intake over a fixed period, usually 1 week, is estimated either by trained workers who visit individual homes or by the person in the household responsible for food preparation who is asked either to re- cord purchases and menus or to recall household food use. Average per capita intakes of food and nutrients are calculated by dividing the total household intake by the number of persons in the family. A major limitation of this method is that it assumes uniform food distribution for members of the individual household. Individual Dietary Data. Of necessity, individual food consumption data must be provided by individual assessments--usually reports from the subjects themselves, but occasionally reports from family members who share their living quarters. Such information is obtained from three basic sources: recent (e.g., 24-hour) recall, food records, or diet history. The recent recall is used most frequently to measure individual consumption. In this method, subjects are asked what foods they con- sumed over a recent specified time--usually 1 to 7 days. The 1-day (or 24-hour) recall only requires that each person estimate the amounts of specific food items consumed during the preceding 24 hours. However, since the foods consumed may vary considerably from one day to the next, 24-hour recalls are more reliable as a source of group data than as a source of individual data, i.e., the average for an entire group is probably reasonably representative of the eating pattern for that group. A 24-hour recall may be recorded by the subject or, more often, by a trained interviewer. He or she may be asked to recall all items or only certain foods eaten during the specified period. One sampling problem is inherent in the 24-hour recall: diets during the weekend may differ greatly from those consumed during the week. To increase the representativeness of the 24-hour recall, this method is often combined with a consumption frequency questionnaire in which subjects are asked how often they eat selected groups of foods. 3 - 4

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34 DIET, NUTRITION, AND CANCER In studies based on food records, participants are asked to main- tain an accurate diary of all foods consumed during a specified period (e.g., 1 week). The subjects must estimate the quantity or weigh or measure each food item eaten at home, allow for inedible portions and plate waste, and note and measure all ingredients in recipes. They must also record estimated amounts of foods consumed away from home. Although the weighed diet record was long viewed as the ideal standard in estimating dietary intake, it requires, at a minimum, a great deal of interest and cooperation on the part of the subjects and, hence, selects for certain types of people. Moreover, this method is likely to cause subjects to modify their eating patterns to some extent, if only for purposes of reducing their work load (e.g., by eating fewer mixed dishes). The accuracy of this method is also compromised in developed countries, where much of the food eaten is neither prepared nor consumed in the home. Finally, this method is unsuitable for very large-scale surveys or studies because of the time and effort involved in providing detailed instructions to the subjects, in making frequent follow-up contacts, and in coding the unstructured information from the records. Despite these limitations, the food record has been used to validate other methods used for collecting dietary intake data in the same study population. Unlike the recent recall, the diet history method does not seek in- formation on intake during a specified day or week but, rather, attempts to determine the average pattern of consumption during a particular per- iod of the subject's life, e.g., just before the onset of an illness. The intake of selected items or the usual dietary pattern for total in- take is obtained through interviews or, less often, by self-administered questionnaire. The information is recorded as frequencies of consumption or, preferably, as estimated total amounts for the period of study. The method requires very thorough training of interviewers (or subjects, if self-administered), careful standardization of the questionnaire, ade- quate allowances for differences in food preparation, and the provision of suitable food models to facilitate quantification. Each of the methods for estimating individual intake has its strengths and weaknesses, but they share certain limitations. People vary in their abilities to estimate exactly how much of something they have eaten, and may sometimes fail to notice (or forget to report) their consumption of certain foods (e.g., side dishes at meals, peanuts taken from a readily available supply). Respondents may also know nothing about the ingredi- ents of the dishes set before them. Furthermore, as mentioned above, they may alter their eating habits when asked to record their intake. In case-control studies, there is an additional problem: subjects who are ill (i.e., cases and sometimes controls) may have altered their diets as a result of their illness. Although patients are generally asked to re- call what they ate before the onset of their illness, they may not be completely successful in this effort. It is especially difficult to relate diet to a disease like cancer, which has a long time course, because we need to learn not only what 3 - 5

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Methodology 35 people ate yesterday or during the previous week, but also what they consumed in the more distant past. (The length of time between expo- sure and onset of disease depends partly on whether the dietary com- ponent being studied is an initiator or promoter.) The notion that subjects can accurately report not only what they usually eat but also what they usually ate is, for the most part, untested, although limited data suggest that "recall" of a diet consumed 20 or more years ago may more closely reflect present food choices than past ones (Garland and Ibrahim, 1981~. There is considerable potential for variation in the technique used by interviewers and the introduction of bias during dietary interviews, especially when very detailed information is required as in studies of cancer. Depending on the hypothesis being tested, the interviewer may need to elicit careful descriptions of food preparation methods, of the fats and oils used for frying, of usual portion sizes, of seasonal vari- ations in intake, etc. Eliciting such information requires considerable probing on the part of the interviewer. During this process, subjec- tivity may be introduced in the recording of responses. For these rea- sons, researchers active in this field spend considerable time training interviewers and developing effective instruments and aids (for example, see Morgan et al., 1978~. Asking subjects for the same information in two or more different ways by using several methods in conjunction with one another may also help to overcome some of these problems. Estimates of quantity can be improved by using realistic or abstract food models (Morgan et al., 1978), photographs of graded portion sizes (Hankin et al., 1975), and similar devices. The strengths and limitations of the major epidemio- logical methods to study effects of diet have been discussed extensively in a number of reports (Beaton et al., 1979; Graham and Mettlin, 1979; Graham _ al., 1967; Hankin et al., 1975; Marr, 1973; Mettlin and Graham, 1978; Morgan et al., 1978; National Academy of Sciences, 1981; Nichols _ al., 1976; Nomura et al., 1976; Reshef and Epstein, 1972~. Biological markers are also used to obtain indirect estimates of individual intakes. This method has the appeal of objectivity, since it entails the direct measurement of substances in serum, tissues, or body wastes as a reflection of actual dietary exposures. Apart from the difficulty in collecting such data from healthy controls, there are other reasons why this method has not been widely used in epidemiological stud- ies of diet and cancer. Foremost is the difficulty of identifying an appropriate indicator of past intake. For example, serum levels of some dietary components, such as cholesterol, do not correlate with informa- tion on intake and may reflect homeostatic balances or long-term patterns of consumption (Pearson, 1967; Underwood et al., 1970~. However, recent reports on vitamin A serum levels suggest that some such measurements may nevertheless be useful in predicting cancer risk in cohort studies (Cambien et al., 1980; Kark et al., 1980; Wald et al., 1980~. A particu- larly troublesome aspect of case-control studies using biological markers 3 - 6

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36 DIET, NUTRITION, AND CANCER (e.g., the relationship of fecal steroids to colon cancer) is that the markers may themselves reflect consequences rather than antecedents of the disease. Analysis of Dietary Data. Regardless of the method used to collect food intake data, the reported foods must be grouped into categories be- fore they can be analyzed. Before this can be done9 some decision must be made concerning the kinds of variables that should be compared with data on the occurrence of cancer. The very first level of decision may be whether to classify the data in terms of foods or nutrients--e."., whether the variable of interest is vitamin C or citrus fruits, carotene or grams of dark green and deep yellow vegetables. In principle, the at the outset of the and forrn~t of the important analytic variables should be idlest; f ; "A ~ study, since that decision will determine the nature and format of the data that are collected. For example, if the variable of interest is total calories from fat rather than the characteristics of specific fats, which may differ according to their sources and processing, then the interviewer need not help the respondent differentiate between animal fats and vegetable oils or between liquid and hydrogenated shortenings. If vitamin C is considered to be the relevant variable rather than fresh citrus fruit, then no effort need be made to sort out the various forms in which oranges might be consumed (e.g., as freshly squeezed or frozen juice, or as whole orange segments). Thus, the nature of the hypothesis determines the nature of the classification used for data collection. This explains much of the discrepant data from different investigations of the same cancer site, although the source of the discrepancy may not be immediately apparent from even the most careful perusal of the pub- lished reports. Since much of the research on the relationship between diet and cancer has been based on hypotheses regarding the effects of nutrients, the raw data on foods consumed has most often been translated into nu- trients, such as grams of protein, animal protein, total fat, satu- rated and unsaturated fat, cholesterol, and complex carbohydrates. The quantitative estimates are usually based on food composition tables, such as those developed by the U.S. Department of Agriculture. (For an example of these estimates, see Morgan et al., 1978.) Unfortunately, the mean values recorded in such sources as USDA Handbook _. 456 (U.S. Department of Agriculture, 1975) may not reflect the specific composition of the foods eaten by subjects in a particular study. For example, wide variations in the nutrient content of unprocessed and processed foods can result from modifications in processing procedures (e.g., the addi- tion or removal of nutrients) over time. However, such inaccuracies will merely tend to weaken any detected association rather than introduce a spurious association. Analyses based on individual foods or food groups are not encumbered by the need to estimate nutrient intake, but are often difficult to in- terpret because of the multiple comparisons involved. In such analyses, the specific substances responsible for an effect may be difficult to identify. 3 - 7

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Methodology 37 Overall Assessment of Epidemiological Approaches The major strength of epidemiological studies is that their focus on human populations circumvents two important limitations of laboratory research. First, since humans are observed directly, the results do not have to be extrapolated from one species to another. Second, since the levels and patterns of exposure studied are those that actually occur among people, interpolation to low doses from the artificially high ex- posure levels frequently required in laboratory research can also be avoided. In addition, since the varieties of human experience produce wide range of exposures to a given risk factor, epidemiological invest) gations are often able to examine directly the effects of different levels of exposure (i.e., dose-response). On the other hand, epidemiological studies present some special difficulties. To begin with, such research is limited by its need to rely primarily on observational data, because it is difficult and often unethical to conduct experiments (i.e., intervention studies) on groups of humans. Furthermore, observational epidemiological studies are open to errors or bias. For example, persons who agree to participate in such studies or who are selected as participants by the investigator (e.g., hospitalized patients) may not comprise truly representative groups of subjects and may yield misleading findings. Unlike studies of cancer among smokers and nonsmokers, dietary stud- ies are confronted with the inherent difficulty of determining reasonably precise exposures. For example, the degree to which cases have been exposed to a particular dietary component may not be sufficiently different from that of controls to demonstrate any effect. Furthermore, it is often difficult to determine the specific dietary constituents to which study participants have been exposed. Another difficulty inherent in epidemiological studies of diet and cancer is the long latency period between first exposure and overt man- ifestation of illness. In case-control studies, this delayed onset makes it necessary for investigators to learn what the subject ate during some period beginning long before the study began, or to assume that recent intakes reflect past exposures. In prospective cohort studies, the in- vestigator must collect current dietary data and then either wait (for up to 20 to 30 years) for the disease to appear or identify sufficiently large groups of subjects for whom there are adequate retrospective dietary data. Accuracy in the measurement of both the exposure and the outcome variables is especially difficult to attain in the studies of diet and cancer. For example, the frequent dependence on recall data from inter- viewed subjects virtually guarantees imprecise measurement of dietary 3 - 8

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38 DIET, NUTRITION, AND CANCER exposure, which might mask small but real differences between cases and controls. Correlation studies may suffer from differences among coun- tries such as completeness of cancer reporting, diagnostic practices, and terminology. Furthermore, because cancer incidence (occurrence) data are frequently not available for such studies, reliance must be placed on mortality data instead. Since mortality reflects survival as well as in- cidence, it is not an ideal measure for cancer etiology, particularly for sites where survival rates are high and have notable international vari- ation. These and other considerations make it especially difficult to identify subtleties in the relationship between the degree of exposure and risk of disease. Most of these deficiencies in epidemiological studies of diet and cancer are likely to result in nondifferential misclassification, thereby reducing the likelihood that a given study will be able to demonstrate true differences that exist between the groups compared. Therefore, the results of epidemiological studies may often be assumed to represent conservative estimates of the true risk for cancer associated with the dietary exposures of interest. LABORATORY METHODS As interest in the possible relationship between diet and cancer has grown in recent years, increasing attention has been paid to the chemical carcinogens in our diet. The foods that we eat contain a vast number of separate chemical entities: several thousand as additives and many times this number as natural constituents. Most of these chemicals are present in relatively low concentrations, but even small amounts of some potent carcinogens might be important if they are present in commonly consumed foods. There are three major laboratory methods for detecting and identify- ing chemical carcinogens: analysis of molecular structure, short-term tests, and long-term bioassays in animals. The first two methods provide information about potential carcinogenicity, whereas the third provides direct evidence of carcinogenicity in laboratory animals. Analysis of Molecular Structure In a review of the large body of evidence pertaining to the role of structure-activity relationships in predicting carcinogenic activity, Miller (1970) suggested that most, if not all, chemical carcinogens are ultimately electron-deficient reactants (Miller, 1970~. Carcinogens have been identified in more than a dozen chemical classes, which share no common structural features (Miller and Miller, 1971, 1979~. Furthermore, even within classes, closely related chemicals may differ with respect to carcinogenicity--e.g., 2-acetylaminofluorene (2-AAF) is a well-known car- cinogen in several species of animals, whereas its close relative 4-AAF is not carcinogenic (Office of Technology Assessment, 1981~. The major 3 - 9

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Methodology 39 utility of the analysis of molecular structure is to screen a variety of chemicals quickly and to treat the results as warnings rather than as definitive indicators of carcinogenic activity. Short-Term Tests Interest in establishing short-term, relatively quick and inexpensive procedures for the identification of chemical carcinogens has increased during the past several years as a result of the realization that the list of potential chemical carcinogens is growing faster than our capac- ity to test the materials (Bridges, 1976~. Therefore, greater numbers of potentially hazardous compounds must be screened and placed into a priority system for further testing. This appears to be the primary role of short-term tests. Since these tests can be conducted quickly (often in only a day or two) and inexpensively, they are useful for screening substances for potential carcinogenicity. For these tests to be useful, they must not only be faster, easier to interpret, more sensitive, and less expensive than the standard feeding studies, but they must also be reliable and relevant to the in viva assay upon which they are modeled. A number of validated short-term tests can be used to examine the capacity of a substance to cause mutations, other genetic alterations, or neoplastic transformation. These tests can be used with a variety of biological systems such as bacteria, yeast, mammalian cells, and intact animals. To date, the most widely used method appears to be the Salmonella/ microsome assay (also called the Ames test), which utilizes several spe- cifically constructed Salmonella typhimurium strains to detect various kinds of mutations and genetic damage (Ames et al., 1975~. It is gen- erally agreed, but not without considerable controversy, that there is a high degree of correlation between the mutagenicity of compounds in the Salmonella/microsome assay and their carcinogenicity in laboratory ani- mals (McCann and Ames, 1976; Purchase et al., 1978; Sugimura et al., 1976~. However, recent studies show that this correlation is dependent upon the class of chemical being investigated. For most aromatic amines, polycyclic aromatic hydrocarbons, and direct alkylating agents, there appears to be a high degree of correlation. On the other hand, chlori- nated hydrocarbons are difficult to identify as mutagens in the Ames test, although they are known to be carcinogenic. In vitro mutagenicity tests have one major drawback: although they may provide a good indica- tion of whether or not an agent is carcinogenic, they produce very little information on its relative carcinogenic potency. Other short-term _ vitro and in viva tests in use include assays for the induction of DNA damage and repair or mutagenesis in bacteria, in yeast, in Drosophila melanogaster, or in mammalian cells in culture. . Whole mammals can be used in the dominant lethal test, mouse spot test, 3-10

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40 DIET, NUTRITION, AND CANCER tests for heritable translocations, and tests for chromosome aberrations. These mammalian mutagenesis bioassays offer promise as prescreening tools since they seem to provide both qualitative as well as quantitative data, but they are more expensive to perform and require more time than the other assays. The _ vitro transformation systems are potentially useful for screening carcinogens, but they are also expensive and time-consuming. Moreover, the reliability of early markers of oncogenic transformation is unknown. If the _ vitro transformation tests have to be carried out to the point of injecting presumably transformed cells into a syngeneic ani- mal to determine if the cells develop into a tumor, then the expense and time involved are the same or possibly greater than required for some in viva carcinogenicity test systems. In general, short-term tests have a number of drawbacks: ~ Carcinogens or modifiers of carcinogenesis may operate by mecha- nisms not involving DNA damage and repair. Thus, some agents, e.g., tumor promoters, which are particularly relevant when one considers diet, are not likely to be detected by these tests. O The effects of absorption, transport, activation, detoxification, and excretion are not taken into account. ~ Quantitative risk assessment cannot be made easily. O Despite positive results for mutagenicity in a battery of such tests, many scientists do not accept such evidence alone as an indica- tion of carcinogenicity. Long-tenm bioassays in whole animals are still necessary to make this determination (International Agency for Research on Cancer, 1980~. Long-Term Bioassays These tests, which are conducted in animals, have been the most widely accepted methods for determining the carcinogenic effect of substances. In the absence of data on humans, all substances demon- strated to be carcinogenic in animals are regarded as potential car- cinogens for humans, and the empirical evidence overwhelmingly supports this hypothesis. The standard procedure in long-term bioassays is to feed substances at levels that are just below the maximum tolerated dose for a major portion of the lifespan of the animal (usually rodents, which have a lifespan of 2 to 3 years). The rationale for feeding very high doses of a substance in chronic bioassays is that the number of animals that de- velop cancer increases as the dose of the test substance is increased. To conduct a valid experiment at high doses, only a small number of ani- mals (a few hundred) is required. An important variable that determines the outcome in these tests is the potency of the carcinogen: the greater 3-11

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The Relationship Between Nutrients and Cancer 55 There are some data indicating the magnitude of the changes in per capita intake of certain food items and constituents; however, many of the changes are not adequately documented. For example, there are no data on the consumption of whole wheat flour, commercial baby food, or home-produced vegetables. Moreover, there is no indication whether fresh vegetables eaten in the Northeast were grown in that region or whether they were shipped by train from California or by air from Mexico (Brewster and Jacobson, 1978~. A variety of differences in their chemical composition (e.g., in their vitamin and mineral content) can result from differences in the way in which these vegetables were grown, transported, and stored. Between 1940 and 1977, per capita intake of food color additives increased tenfold. Soft drink consumption increased 1.5 times in just 16 years--between 1960 and 1976 (Brewster and Jacobson, 1978~. Although total intake of fruits and vegetables increased slightly between 1909 and 1976 (Table A-2), the intake of fresh fruits and vegetables] actually declined (Table A-3), a major portion of that decline having occurred after 1948. Changes in the per capita intake of certain individual commodities are especially striking. For example, the intake of fresh potatoes is more than two-thirds lower than it was at the turn of the century and more than one-half lower than it was 30 years ago, whereas the intake of processed potatoes has increased by a factor of 44 during the same 30 years. The per capita intake of pro- cessed citrus fruit juice--which accounts for much of the increase in overall fruit intake--increased dramatically from an average of less than one 4-oz (120-ml) serving per person annually in 1948 to 117 4-oz servings per person in 1976 (Brewster and Jacobson, 1978~. Similarly, the intake of canned or bottled tomato products (e.g., paste, sauce, catsup, and chili sauce) increased from 2.25 kg per capita in 1920 to 10.1 kg per capita in 1976 (Brewster and Jacobson, 1978~. All of these changes reflect the proliferation of food products on the market--from less than 1,000 at the end of World War II to well over 10,000 at present (Molitor, 1980~. The term "fresh" applied to fruits and vegetables commonly refers to produce that has been, at most, washed, trimmed, and chilled. The term "processed" has many meanings; for example, preservation by canning and freezing, which result in some chemical but little structural change; extraction and dehydration such as the preparation of orange juice con- centrate, which produce significant structural and possibly major chemical changes including nutrient loss; and processes that involve extensive separation of foods into components, or the fabrication of new foods such as "chips" made from molded rehydrated potato flakes, which result in marked structural changes that may have equally marked effects on the chemical composition of foods. A-5

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56 DIET, NUTRITION, AND CANCER TABLE A-3 Annual Per Capita Intake of Fresh and Processed Fruits, Potatoes, and Other Vegetables in the United Statesa Annual Consumption, kg/Person Vegetables Fruits (Excluding Potatoes) Potatoes Year Fresh Processed Fresh Processed Fresh Processed 1909 75.6 3.61 83.7 7.7 81.9 0.2 1927 76.5 8.1 85.5 11.7 63.9 0.2 1948 73.8 19.8 82.8 21.15 50.0 0.2 1965 4 7. 3 27.5 63.5 29.7 30.6 5.4 1976 52.7 36.5 65.3 31.1 24.3 9.9 aAdapted from Page and Friend, 1978. These striking changes in the food supply need to be taken into account when one examines the relationship between diet and cancer. On the one hand, any change in cancer incidence resulting from major changes in food processing that occurred before 1900 (e.g., roller milling of grain) or up to 40 years ago (e.g., flour enrichment) would probably have been observed long before now. Conversely, because of the long latent period between exposure and manifestation of cancer, effects from changes introduced less than 10 years ago might not yet be evident. If, as is often the case, changes in food-processing methods are poorly monitored, the extent of exposure to substances resulting from those processes will not be known. In such cases, it will be difficult to make any associations between those substances and cancer incidence. A more difficult problem is encountered in case-control studies: here one must determine what foods were consumed by subjects one or more decades in the past. It is necessary to make one of two assump- tions when collecting such information: that people can accurately remember their typical dietary patterns of 10 or more years ago, or that present diets adequately reflect diets consumed in the past. Both of these assumptions are most subject to inaccuracies when there have been continual shifts in the numbers, types, and varieties of available foodstuffs. Even when the kinds and amounts of foods consumed in the past can be accurately determined, their chemical composition remains - ~ ~ ~ For example, a frozen pizza made with imitation cheese, tomato extender, and soy-protein pepperoni is composed of a very different collection of chemicals than the apparently similar product made 10 years earlier with mozzarella cheese, tomato paste, and meat sausage. A-6 unknown and may have chanced significantly over the decades. ~ . .

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The Relationship Between Nutrients and Cancer 57 The proportion of manufactured products in the average diet has been increasing, especially in developed countries, but the detailed composition of many of these products is not known. Manufacturers often consider it proprietary information. Figures on the production of ascorbic acid illustrate both the scale of the potential effects of processing and the difficulty of monitoring such effects (Table A-4). During the past 20 years, there has been a sixfold increase in the tonnage of ascorbic acid produced. But in standard food composition tables prepared by the U.S. Department of Agriculture, only the amount of ascorbic acid used for food fortification is recorded. The disposi- tion of the remainder is unknown. Most of the imbalance is probably consumed in the form of vitamin supplements. Nonetheless, the fact remains that large amounts of ascorbic acid, as well as other nutrients, are added to foods for "technical" reasons, e.g., for their antioxidant ~' ' ~ "nutritional" reasons. These amounts do not , . , show up on tables of nutritional value, although vitamins are monitored nore carefully than most other components of the food supply. Most non- nutritive substances are not monitored at all, and as a consequence almost nothing is known about their presence or fluctuations over tine. Saccharin, for example, is a nonnutritive substance intentionally added ' ~ ~~~ i-- ~~ ~ themselves--and, to a Properties. as opposed to ~ - , to food--by manufacturers or by the consumers very large extent, it is knowingly consumed. Yet, in epidetniological studies it has proved very difficult to obtain reliable data on indi- vidual saccharin intake. Obviously, it is even snore difficult to obtain consumption data for substances that are neither monitored, as are the nutrients, nor consumed intentionally, as is saccharin. TABLE A-4 Production of Ascorbic Acid in the United Statesa Year 1960 1965 1970 1974 1982 Amount Produced (Metric Tons) 2,392 3~914 5,470 1O3O54 14~800 (estimated) aData from U.S. International Trade Commission, 1980. A-7

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58 DIET, NUTRITION, AND CANCER Because of this paucity of information, it is possible to make only the crudest assessments of factors that may affect the composition of foods. For example, one can determine whether fruits are available fresh, frozen, or canned, whether potatoes are available fresh or dried, but not whether macaroni contains soy flour or whether tomato paste contains modified starch, 6-carotene (for color), and added vitamin C--among other things. It is not clear whether all the changes in the food supply have increased, decreased, or had no effect on the incidence of cancer. Overall U.S. cancer rates at most sites other than lung and stomach have remained relatively stable for several decades. This might suggest that the food supply has contained an unchanging cluster of cancer-causing or protective substances throughout much of this per- iod, despite the extensive changes in the composition and quantity of many of the foods consumed. It is also possible that any changes capable of affecting cancer rates (positively or negatively) have occurred too recently to be reflected in cancer statistics. But even if cancer rates rise or fall in the future, it may prove very diffi- cult to identify which, if any, specific compositional modifications are involved, since so many different changes are going on simultane- ously. This is illustrated in Figures A-2 and A-3, which show the changing sources of fat in the U.S. diet. These figures reveal that the relatively stable consumption of "total table spreads" and "total cooking fats" masks a dramatic shift in the sources and, hence, the composition of the fats involved. The use of butter and lard has decreased sharply, whereas margarine and shortening (usually based on vegetable oil) have come into much wider use (Brewster and Jacobson, 1978). 20 - , 1 5 Q A) Q En ~ 10 o - y 5 o :\ OCR for page 30
The Relationship Between Nutrients and Cancer 59 25 20 Total Cooking Fats o In o, 15 = - cn `' 10 o J 5 _ O , 1 , 1 , 1 , 1 , 1 , 1 ,. 1 1910 1930 1950 1970 ~ 1 976 i_ . , _ Shortening / ~_~ i./ _ ~ i \ ~ Lard 1 Q30 1 950 YEAR FIGURE A-3. Intake of cooking fat. From Brewster and Jacobson, 1978. At any particular time, cancer rates probably reflect the sum of many changes, some producing positive and others negative effects. For example, the introduction and subsequent wide use of refrigeration and the increased use of mold-inhibitors and antioxidant s have probably had ~ ~ Together, these changes have markedly decreased the positive effects. population's exposure to rancid and/or moldy foods and to foods preserved by salting, smoking, or drying. , - The effect of other changes is less clear. Although there has been relatively little change in the overall percentage of calories derived from fat, protein, and carbohydrate, there have been marked shifts in consumption patterns from vegetable to animal protein, from complex to simple carbohydrates, and, as already noted, from animal to vegetable fats. The increase in per capita intake of fat from meat has compen- sated for a decline in the intake of dairy fats. In addition, there has been a marked increase in the intake of separated vegetable oils that have been structurally altered by hydrogenation and other treatments. A-9

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60 DIET, NUTRITION, AND CANCER There have also been changes in the nature of the fat-soluble contaminants present in the diet. In federal inspections for pesti- cide residues, contaminants have been found most frequently in meats and fats (U.S. Food and Drug Administration, 1980~. The Comptroller General (1979) reported that of 143 drugs and pesticides likely to leave residues in raw meat and poultry, 42 were known to cause or suspected of causing cancer. Twenty years ago, fats were much less likely to carry such residues since the use of both drugs in animals and pesticides has increased markedly in the interim (Smith, 1980~. A fivefold increase in the per capita intake of french-fried potatoes is part of a trend toward a much greater consumption of products crisped by exposure to heated fat or to extreme dry heat. Such products include potato chips, fried snacks, crackers, and ready-to-eat breakfast cereals. Many products of such browning reactions have proved to be mutagenic in laboratory tests as have the by-products resulting from the frying and broiling of meat and fish (see Chapter 13~. Hence, products in this category must be regarded as potential contributors to carcinogenesis. Several other changes may also be important, but their effects on carcinogenesis are not known. For example, there has been a documented decline in the consumption of certain types of vegetables, especially in their fresh state. The effect, if any, of the marked increase in the consumption of cooked (and often burned) tomatoes is also unclear as is the effect of the documented decline in the consumption of fresh cabbage, since the total long-term consumption of other cruciferous vegetables (e.g., broccoli, cabbage, and kale) is impossible to cal- culate given the lack of accurate data on home production. However, the documented decrease in the annual per capita intake of sweet potatoes, from 11.1 kg per person during 1976 to 2.4 kg during 1980, combined with the declining consumption of fresh dark green and deep yellow vegetables, has very likely decreased the intake of dietary fiber and naturally occurring 6-carotene, which recently have been studied for their possibly protective roles in carcinogenesis (Chapters 8 and 9~. Despite (or perhaps because of) the paucity of information pertain- ing to the composition of our contemporary food supply, foods have been most often used in epidemiological studies as indicators of the presence of particular nutrients or they have been grouped for analysis accord- ing to certain nutrients they have in common. Given the multitude of other chemicals present in the diet, it is notable that epidemiological studies have found significant relationships between the occurrence of cancer and estimated intakes of such nutrients as fat, vitamins A and C, or protein (see Chapters 5, 6, and 9~. This would seem to indicate either that these nutrients must play a role in the development of cancer or that they serve as indicators of other substances that do. Epidemiological associations between cancer and nutrients are often based on the presence in the diet of certain foods. For example, citrus fruits have sometimes been used as indicators of A-10

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The Relationship Between Nutrients and, Cancer 61 the presence of vitamin C, although they obviously have much more in common than ascorbic acid. They contain, among other substances, flavonoids (Chapters 13 and 15~. The dietary presence of vitamin A has often been based on green and yellow vegetable consumption (Chapter 9), although the active agent in those foods may not actually be vitamin A. Peto _ al. (1981) suggested that carcinogenesis may be inhibited by 6-carotene (the plant constituent that can be converted to vitamin A in the body), rather than by the vitamin itself. Their report suggests that, when examining naturally occurring compounds in foods, we should not limit our attention to those already identified as having a nutri- tional role. Until fairly recently, fiber was also overlooked as a possible protective factor in carcinogenes~s. For many years, fiber was re- garded as a collection of inert substances in foods, even though it was known to be present in relatively large amounts, compared to vitamins and minerals. These substances were even regarded as a nuisance factor that might interfere with the absorption of minerals in unrefined diets Since most traditional diets contain large amounts of such indigestible residues, fiber came to scientific attention as a result of observa- tions that peoples consuming "primitive" diets high in complex carbohy- ates (including fiber) appear to be spared a number of maladies, includ- ing bowel cancer, that are common to populations consuming more refined diets. These simple observations have led to ongoing investigations con- cerning which components of carbohydrate should "count" as fiber, which of them might play a role in carcinogenesis, and how (or whether) fiber affects the incidence of certain diseases or whether it acts merely by displacing other dietary substances that are either carcinogens or promoters of carcinogenesis. The recent findings concerning fiber remind us again that sub- stances in food other than those presently classified as nutrients may be instrumental in the development of cancer. Milk is one major food that is difficult to classify in cancer studies. As a source of vitamin A (Mettlin and Graham, 1979), whole milk may be a beneficial component of the diet; but as a source of fat (Blair and Fraumeni, 1978 Howell, 1974), it may have deleterious consequences. The category "dairy products" or "milk products" may combine milk products such as butter, cheese, cream, yogurt, low-fat milk, and cottage cheese, some of which are very different from each other in composition. In a case- control study conducted by Phillips (1975), dairy products other than milk were associated with breast cancer. Hirayama (1977) reported that the ingestion of two glasses of milk daily was associated with a lower risk of gastric cancer in a large cohort. There have been surprisingly few studies linking specific foods with either increases or decreases in cancer rates. Where there have been such studies, e.g., those on cruciferous vegetables, the data A-11

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62 DIET, NUTRITION, AND CANCER underscore the fact that it will be difficult for epidemiologists to sort out the specific chemicals of concern. For example, the consti- tuents of cruciferae responsible for their apparent effect on the occurrence of cancer may be, as Chapter 15 suggests, indoles, isothio- cyanates, or other nonnutritive substances demonstrated to affect car- cinogenesis in the laboratory. But it is not yet possible to attribute the epidemiological associations to any such substances simply because of the simultaneous presence in these vegetables of such other consti- tuents as fiber, 6-carotene, ascorbic acid, or calcium. Moreover, the identification of these associations is complicated not only by the composite nature of single foods but also by the in- terrelated variations in the intakes of a number of foods in any given diet. By eating more broccoli, one ordinarily eats less of something else. More broadly, those who increase their consumption of vegetable products must, of necessity, simultaneously reduce their consumption of animal products since these are the only two classes of substances (other than table salt and water) ordinarily consumed by humans. A reduced intake of animal products will normally result in a decreased consumption of nutrients such as animal fat, animal protein, heme iron, preformed vitamin A, and zinc; of mutagens formed during the cooking of meat; and of such fat-soluble contaminants as pesticides and drugs used for animals. This tendency for certain nutrients and other substances to occur together in certain types of foods accounts for the strong direct correlations among such dietary variables as beef, all meats, animal fat, and animal protein in epidemiological studies. Moreover, a reduced intake of animal products is necessarily accompanied by an increased intake of substances such as starches, fibers, and certain vitamins and minerals that are present in the substituted vegetable foods. Since all these dietary constituents increase and decrease simultaneously, it is difficult to determine which ones, if any, are involved when, for example, consumption of animal products and cancer rates decrease simultaneously or when control subjects consume more animal products than do cancer cases. Individual diets are not composed of isolated substances or even isolated foods but, rather, they contain thousands of unique combina- tions of nutrients and other compounds that comprise the individual food items. From the standpoint of public education and public health, therefore, it is considerably less important to identify isolated com- pounds that cause or protect against certain cancers than it is to identify dietary patterns that enhance or minimize overall risk. The conclusions and recommendations contained in Chapter 1 reflect this committee's assessment of the evidence regarding some components of these patterns. SUMMARY AND CONCLUSIONS Since the turn of the century, there have been extensive changes in foodstuffs consumed by the U.S. population. Only a few of these A-12

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The Relationship Between Nutrients and Cancer 63 changes have been measured, and then only crudely. Levels of nutrient intake that have been monitored have remained relatively constant between 1909 and the present, but data indicate that this constancy obscures major unmeasured changes in intake of other substances result- ing from the declining consumption of certain commodities; changes in the forms in which foods are consumed; or the introduction of entirely new products and substances. The relationship between these changes in the food supply and the incidence of cancer is not yet clear. The fact that the food supply has undergone major changes while the rates of cancer at most sites have been relatively constant may suggest that none of the changes has an effect on cancer incidence, that the changes have occurred too recently to produce an effect, or, more likely, that some changes have had a positive and some a negative impact. Data reviewed in this re- port indicate that a number of substances in food other than nutrients may play a role in the causation or the prevention of cancer. Thus, it may be important in epidemiolgical studies to consider a variety of food classifications and to monitor changes in the food supply in addition to those that affect nutrients. A-13

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64 DIET, NUTRITION, AND CANCER REFERENCES Blair, A., and J. F. Fraumeni, Jr. 1978. Geographic patterns of prostate cancer in the United States. J. Natl. Cancer Inst. 61:1379-1384. Brewster, L. M., and M. Jacobson. 1978. The Changing American Diet. Center for Science in the Public Interest, Washington, D.C. 80 pp. Comptroller General. 1979. Problems in Preventing the Marketing of Raw Meat and Poultry Containing Potentially Harmful Residues. Comptroller General's Report to the Congress of the United States, No. HRD-79-10, April 17, 1979. General Accounting Office, Washington, D.C. 87 pp. Hirayama, T. 1977. Changing patterns of cancer in Japan with special reference to the decrease in stomach cancer mortality. Pp. 55-75 in H. H. Hiatt, J. D. Watson, and J. A. Winsten, eds. Origins of Human Cancer, Book A: Incidence of Cancer in Humans. Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y. Howell, M. A. 1974. Factor analysis of international cancer mortality data and per capita food consumption. Br. J. Cancer 29:328-336. Mettlin, C., and S. Graham. 1979. Dietary risk factors in human bladder cancer. Am. J. Epidemiol. 110:255-263. Molitor, G. T. T. 1980. The food system in the 1980s. J. Nutr. Educ. 12 (Suppl. 1~:103-111. Page, L., and B. Friend. 1978. The changing United States diet. Bioscience 28 :192-197. Peto, R., R. Doll, J. D. Buckley, and M. B. Sporn. 1981. Can dietary carotene materially reduce human cancer rates? Nature 290:201-208. Phillips, R. L. 1975. Role of life-style and dietary habits in risk of cancer among Seventh-Day Adventists. Cancer Res. 35:3513-3522. Smith D. T. 1980. Antibiotic additives: The prospect of doing without. Farmline 1~9~:14-15. U.S. Food and Drug Administration. 1980. Compliance Program Report of Findings. FY 77 Total Diet Studies--Adult (7320.73~. Bureau of A-14

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~e R^~~ Be- -~ ~d ~~ ~ Foods, food and Drug Administration, U.S. Department of Health, Education, and Welfare, Washington, D.C e [ 33] pp. Ue S" International Trade Co _ fission. 1980. Synthetic Organic Chemicals. United States Production and Sales, 1980 e USITC Publication 1183e Office of Industries, OeSe International Trade Co _ ission, Washington, D eC e 327 pp e A-15